Since the early 1940""s penicillins, and more recently cephalosporins, have been utilized in man""s fight against bacterial infections. These two classes of molecules were the first effective treatments for life threatening infections. Over the past 50 years a tremendous effort has been expended by the scientific community to develop increasingly effective forms of these antibiotics. This effort has led to the identification of specific molecules of great importance to the global medical community. Cefaclor and cephalexin are two examples of cephalosporin antibiotics that have been developed through this process. Despite years of continuing research on new antibiotics, many penicillins and cephalosporins are still widely utilized in the every day fight against pathogenic bacteria.
The primary drawbacks associated with cephalosporins relate to the difficulty and expense of their synthetic production. Several of these important compounds are derived through the synthetic transformation of a penicillin substrate which is itself acquired through a fermentation process. Many steps in the conversion of penicillins to cephalosporins are typically performed using reagents which pose a number of health and environmental risks. In addition, these reagents present economic disadvantages of high outright cost as well as a high cost associated with disposal of the generated waste. These factors significantly affect the overall cost of producing cephalosporin antibiotics.
The present invention relates to novel processes for the preparation of 3-methylenecephams. The present invention utilizes specific catalysts and novel intermediates which have a member of advantages over the analogous procedures known in the art. These catalysts are typically utilized in a less than stoichiometric amount, which may also be recovered and reused, thereby allowing for lower material costs as well as significantly lower waste disposal costs. These two important features combine to lower the overall production cost of 3-methylenecephams and some novel starting materials even eliminate the need for catalysts at all. More specifically, the present invention relates in part to the intramolecular cyclization of penicillin sulfoxide derived monocyclic azetidinone derivatives either thermally or with metal salt catalysts.
The present invention is directed to a process of preparing compounds of the formula I: 
said process comprising the step of reacting a compound of the formula II; 
with a catalyst of the formula III in an inert solvent;
wherein:
M is Sc, Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Zr, Hf, Th, Nb, Ta, U, Bi, or In;
E is O[SO2(C1-C6 polyfluoroalkyl)], N[SO2(C1-C6 polyfluoroalkyl)]2, or C[SO2(C1-C6 polyfluoroalkyl)]3;
x is the common oxidation state of the metal M;
y is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;
R is a carboxylic acid protecting group;
Rxe2x80x2 is hydrogen or a carboxylic acid protecting group;
R1 is a group of the formula; 
R2 is C2-C4 alkenylene, C2-C4 alkylene, 1,2-phenylene, or 1,2-cyclohexenylene;
R2xe2x80x2 is C1-C3 alkyl, C1-C6 haloalkyl, C1-C3 alkoxy, or 2,2,2-trichloroethoxy;
R3 is hydrogen, C1-C3 alkyl, halomethyl, cyanomethyl, 3-(2-chlorophenyl)-5-methylisoxazol-4-yl, benzyloxy, 4-nitrobenzyloxy, 2,2,2-trichloroethoxy, tert-butoxy, 4-methoxybenzyloxy, phenyl, substituted phenyl, a group of the formula R0xe2x80x94(Q)mxe2x80x94CH2xe2x80x94, a heteroarylmethyl group of the formula Rxe2x80x3CH2xe2x80x94, or a substituted arylalkyl group of the formula 
R0 is phenyl, substituted phenyl, 2-thienyl, 3-thienyl, or 1,4-cyclohexyldienyl;
Rxe2x80x3 is 2-furyl, 3-furyl, 2-thiazolyl, or 5-isoxazolyl;
m is 0 or 1,
Q is O or S;
W is protected hydroxy, or protected amino;
Y is hydrogen, acetyl, or nitroso;
X is chloro, bromo, xe2x80x94OR4, xe2x80x94SR5, or xe2x80x94NR6R7 wherein: (a) R6 is hydrogen and R7 is hydrogen, phenyl, substituted phenyl, or xe2x80x94NHR8; or wherein (b) R6 is xe2x80x94COOR9 or xe2x80x94COR9 and R7 is xe2x80x94NHxe2x80x94COOR9 or xe2x80x94NHxe2x80x94COR9; or wherein (c) R6, R7, and the nitrogen to which each is attached combine to form an imido group of the formula 
R4 is hydrogen, C1-C10 alkyl, (C1-C3 alkyl)aryl, C1-C6 haloalkyl, or xe2x80x94COR10;
R5 is C1-C6 alkyl, phenyl, substituted phenyl, (C1-C3 alkyl)phenyl, or (C1-C3alkyl)substituted phenyl;
R8 is aminocarbonyl, C1-C3 alkylaminocarbonyl, C1-C3 alkoxycarbonyl, C1-C3 alkylcarbonyl, or tosyl;
R9 is C1-C6 alkyl, or phenyl;
R10 is C1-C6 alkyl, C1-C6 polyfluoroalkyl, C3-C6 cycloalkyl, adamantyl, phenyl, substituted phenyl, (C1-C3 alkyl)phenyl, or (C1-C3 alkyl)substituted phenyl, or a group of the formula 
Z is solid polymer support; and
Z1 is one or two groups independently selected from the group consisting of hydrogen, halo, hydroxy, protected hydroxy, nitro, cyano, trifluoromethyl, C1-C4 alkyl, and C1-C4 alkoxy.
The present invention is also directed towards the novel compounds of Formula IIA below: 
R is a carboxylic acid protecting group;
R1 is a group of the formula; 
R2 is C2-C4 alkenylene, C2-C4 alkylene, 1,2-phenylene, or 1,2-cyclohexenylene;
R2xe2x80x2 is C1-C3 alkyl, C1-C6 haloalkyl, C1-C3 alkoxy, or 2,2,2-trichloroethoxy;
R3 is hydrogen, C1-C3 alkyl, halomethyl, cyanomethyl, 3-(2-chlorophenyl)-5-methylisoxazol-4-yl, benzyloxy, 4-nitrobenzyloxy, 2,2,2-trichloroethoxy, tert-butoxy, 4-methoxybenzyloxy, phenyl, substituted phenyl, a group of the formula R0xe2x80x94(Q)mxe2x80x94CH2xe2x80x94, a heteroarylmethyl group of the formula Rxe2x80x3CH2xe2x80x94, or a substituted arylalkyl group of the formula 
R0 is phenyl, substituted phenyl, 2-thienyl, 3-thienyl, or 1,4-cyclohexyldienyl;
Rxe2x80x3 is 2-furyl, 3-furyl, 2-thiazolyl, or 5-isoxazolyl;
m is 0 or 1,
Q is O or S;
W is protected hydroxy, or protected amino;
Y is hydrogen, acetyl, or nitroso;
R10 is C1-C6 alkyl, C1-C6 polyfluoroalkyl, C3-C6 cycloalkyl, adamantyl, phenyl, substituted phenyl, (C1-C3 alkyl)phenyl, diphenylmethyl, or (C1-C3 alkyl)substituted phenyl, or a group of the formula 
Z is solid polymer support; and
Z1 is one or two groups independently selected from the group consisting of hydrogen, halo, hydroxy, protected hydroxy, nitro, cyano, trifluoromethyl, C1-C4 alkyl, and C1-C4 alkoxy.
The present invention is also directed towards a process of preparing a compound of Formula I, as described above, wherein said process comprises heating a compound of the Formula IIA, as described above, to a temperature of about 40xc2x0 C. to about 200xc2x0 C.
The term xe2x80x9cC1-C10 alkylxe2x80x9d as used herein includes both straight and branched alkyl groups; including but not limited to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and the like. Included within the definition of xe2x80x9cC1-C10 alkylxe2x80x9d are also the groups xe2x80x9cC1-C8 alkylxe2x80x9d, xe2x80x9cC1-C6 alkylxe2x80x9d, xe2x80x9cC1-C5 alkylxe2x80x9d, xe2x80x9cC1-C4 alkylxe2x80x9d, and xe2x80x9cC1-C3 alkylxe2x80x9d.
The term xe2x80x9calkoxyxe2x80x9d as used herein designates an alkyl group attached through an oxygen atom. Examples include but are not intended to be limited to methoxy, ethoxy, pentoxy, and the like.
The term xe2x80x9cC1-C3 alkoxycarbonylxe2x80x9d as used herein includes, but is not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and isopropoxycarbonyl.
The term xe2x80x9cC1-C6 polyfluoroalkylxe2x80x9d as used herein includes both straight and branched alkyl groups; including but not limited to methyl, ethyl, propyl, butyl, pentyl, hexyl, which are substituted with from 2-13 fluorine atoms. The number of fluorine atoms will never exceed the available valency of the alkyl group. For example, a methyl group could be substituted with 2 or 3 fluorine atoms, an ethyl group with 2-5 fluorine atoms, and a propyl group with 2-7 fluorine atoms. Substitution can occur independently at any of the available cites.
The term xe2x80x9chaloxe2x80x9d as used herein includes fluoro, bromo, chloro, and iodo.
The term xe2x80x9cprotected aminoxe2x80x9d as employed herein represents amino groups in which the either one or both of the amine hydrogens have been exchanged with a commonly employed protecting group. Protecting groups of this type are well know in the art and are additionally described in: T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and sons, (1981) and T. G. Greene and P. Wutz, Protective Groups in Organic Synthesis, second ed. Preferred amino protecting groups include but are not limited to tert-butoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl or the 1-carbomethoxy-2-propenyl group formed with methyl acetoacetate.
The term xe2x80x9cprotected hydroxyxe2x80x9d as used herein refers to the readily cleavable groups formed with a hydroxy group such as formyloxy, chloroacetoxy, benzyloxy, benzhydryloxy, trityloxy, 4-nitrobenzyloxy, trimethylsilyloxy, phenacyloxy, tert-butoxy, methoxymethoxy, tetrahydropyranyloxy, and the like. Other hydroxy protecting groups are well know in the art and are additionally described in Greene.
The term xe2x80x9ccarboxylic acid protecting groupxe2x80x9d as used herein refers to the commonly used groups employed to block or protect the carboxylic acid functionality while reactions involving other functional sites are carried out. Such groups are well know in the art and are additionally described in Greene. They include by way of example but are not intended to be limited to the following: methyl, tert-butyl, benzyl, 4-methoxybenzyl, allyl, C2-C6 alkanoyloxymethyl, 2-iodoethyl, 4-nitrobenzyl, diphenylmethyl (benzhydryl), phenacyl, 4-halophenacyl, dimethylallyl, 2,2,2-trichloroethyl, and the like. Carboxylic acid protecting group strategies have been utilized with penicillins and cephalosporins for over 50 years and it is important to note that a skilled artisan in the art would appreciate which protecting groups are commonly utilized in this well known area of chemistry.
The term ""substituted  as used herein refers to a group which is substituted with 1 or 2 substituents dependently selected from the group consisting of halo, hydroxy, protected hydroxy, nitro, cyano, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, amino, or protected amino. Examples of substituted phenyl include but are not intended to be limited to the following: 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, and the like. A protected hydroxyphenyl would include by way of example but is not limited to 4-tetrahydropyranyloxyphenyl, 4-(4-nitrobenzyloxy)phenyl, 2-phenacyloxyphenyl, 4-benzyloxyphenyl, 3-benzyloxyphenyl, 4-tert-butoxyphenyl, 4-benzhydroxyphenyl, 4-trityloxyphenyl, 4-tert-butyldimethylsilyloxyphenyl, and the like. Nitrophenyl groups are 2-nitrophenyl, 3-nitrophenyl, and 4-nitrophenyl. By way of example other substituted groups would include benzyl, aryl, and the like. Importantly, the substituents can be independently selected so that groups like 4-bromo-3-methoxyphenyl, 4-trityloxy-2-nitrophenyl, and the like are included herein.
The term xe2x80x9c(C1-C3 alkyl) phenylxe2x80x9d as used herein refers to C1-C3 alkyl group substituted with a phenyl group. Likewise any group in xe2x80x9c( )xe2x80x9d links the functional groups immediately proceeding and following that group.
In the forgoing definitions, hydroxy, amino, and carboxy protecting groups are not exhaustively defined. The function of such groups is to protect the reactive functional groups during the course of the reaction sequence and then be removed at some later time without disrupting the remainder of the molecule. A skilled artisan would appreciate that a wide variety of protection strategies would be applicable to the present invention many of which are well know in the art and have been extensively studied and published.
Imido groups represented when R2 is C2-C4 alkenylene are maleimido, 3-ethylmaleimido, 3,4-dimethylmaleimido, and like imido groups. Imido groups represented when R is 1,2-cyclohexenylene or 1,2-phenylene are 3,4,5,6-tetrahydrophthalimido or phthalimido (Ft) respectively.
Preferred Embodiments
Preferred compounds of the formula II or IIA for use in present invention include compounds wherein:
R is
a) a penicillin or cephalosporin carboxylic acid protecting group,
b) p-nitrobenzyl,
c) p-methoxybenzyl,
d) C1-C6 alkyl,
e) substituted C1-C6 alkyl,
f) phenyl,
g) substituted phenyl,
h) diphenylmethyl,
i) trichloroethyl,
j) benzyl, or
k) substituted benzyl.
R1 is
a) a penicillin or cephalosporin amino side chain,
b) PhOCH2CONHxe2x80x94(Vxe2x80x94), PhCH2CONHxe2x80x94 (Gxe2x80x94), or phthalimido (Ft-)
c) phthalimido.
R10 is
a) C1-C6 alkyl,
b) methyl,
c) t-butyl,
d) substituted C1-C6 alkyl,
e) phenyl,
f) substituted phenyl,
g) dimethylphenyl
h) benzyl,
i) substituted benzyl
j) phenyl bonded to a polymer support.
X is
a) chloro
b) OR4 
c) bromo
Halo is preferably chloro or bromo.
Synthetic Methodology
The penicillin sulfoxide ester precursors to the compounds of formula II are either know, readily available, or described herein; many of which have been utilized in the art for the preparation of cepham compounds. By way of example, they can be prepared from 6-acylamino and 6-imidopenicillin acids by a) esterification and b) subsequent oxidation, usually with MCPBA, peracetic acid, or sodium periodate.
The starting materials used to prepare compounds of formula II are well known in the art and readily prepared by known processes. See for example, S. Kukolja and S. R. Lammert, Angew. Chem., 12, 67-68 (1973); Kukolja U.S. Pat. No. 4,052,387; and Kukolja U.S. Pat. No. 4,159,266 all herein incorporated by reference.
Catalyzed Cyclization 
It has been recognized in the art that other derivatives of azetidinone sulfinyl chlorides can be prepared by known methods, including sulfite esters, thiosulfinate esters, and sulfinamides, and sulfinimides. Such derivatives can be prepared by well-known conventional procedures for making the analogous carboxylic acid derivatives. In addition to cyclizing the sulfinyl chlorides directly, the cyclization methodology of the present invention is applicable and can be directed to such compounds.
The cyclization reaction of the present invention can be catalyzed by a catalyst of the formula III;
MEx(H2O)yxe2x80x83xe2x80x83(III)
wherein M is selected from the group consisting of Sc, Yb, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Zr, Hf, Th, Nb, Ta, U, Bi, or In. E is O[SO2(C1-C6 polyfluoroalkyl)], N[SO2(C1-C6 polyfluoroalkyl)]2, or C[SO2(C1-C6 polyfluoroalkyl)]3; x is the common oxidation state of the metal M; and y is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9. A skilled artisan would appreciate that the lanthanides would be applicable to the present invention. Preferred metals (M) include Hf, Sc, Zr, Bi, and Yb; the most preferred is Yb. E is preferably O(SO2CF3). E is also preferably N(SO2CF3)2. Preferably x is 3, and y is 0 or 3 The molecules of water associated with the catalyst will vary depending on the particular metal (M) utilized and its oxidation state. The catalyst""s level of hydration may or may not be crucial depending on the circumstance of the reaction and is typically determined by the stability of the particular complex and is primarily based on convenience and availability. The level of hydration is typically from 0-4 moles per mole of catalyst.
The temperature at which the cyclization of the present invention is performed is not crucial and can vary depending on the reactivity of both the catalyst and the particular compound of formula II which is being cyclized. The process is most preferably performed at room temperature. Alternatively, a temperature range from about 10xc2x0 C. to about 50xc2x0 C. is preferred. Alternatively, the process can be performed at the reflux temperature of the solvent medium, which would typically range from about 50xc2x0 C. to about 200xc2x0 C. Most preferably a reflux temperature would be from about 70xc2x0 C. to about 120xc2x0 C. A skilled artisan would appreciate that the exact temperature of the reaction is not crucial as long as the rate of the cyclization is sufficient to provide a reasonable half-life of the starting material and product. Often one may choose a slightly lower reaction temperature, including sub-ambient temperatures, to avoid detrimental side reactions that would lower the overall yield and purity of the product. Given specific compounds of formula II and III temperatures as low as 0xc2x0 C. may be appropriate.
Similarly, the solvent chosen for the reaction is not crucial. The solvent must be substantially inert to the other reactants and sufficiently effective to dissolve the reactants allowing them to react. The reaction need not, and may preferably not, be homogenous. A wide variety of polar and non-polar solvents may be utilized in the present invention. Choice of appropriate solvent will be determined by the characteristics of the particular compounds of formula II IIA and III, as well as the temperature at which one seeks to run the process. Preferred solvents include nitromethane, acetonitrile, tetrahydrofuran, ethers, alkanes, and mixtures thereof. Most preferred solvents include nitromethane, and acetonitrile, and mixtures thereof. Most preferred compounds of Formula II are those wherein X is chloro.
Preparation of Compounds of Formula IIA
The compounds of Formula IIA can be prepared by techniques known in the art and according to the following scheme. 
Protected penicillin sulphoxide is converted to the corresponding protected sulphinyl chloride by procedures well know in the art (see Kukolja supra). The reaction is preferably performed utilizing N-chlorosuccinamide or N-chlorophthalimide in e.g. toluene, dichloroethane or carbon tetrachloride at reflux from about 20 minutes to 1 hour. The chloride can then be displaced by the metal salt of a carboxylic acid to form the compounds of formula IIA, wherein R10 is preferably derived from a hindered carboxylate salt. Preferred salts include sodium, potassium, and silver but a skilled artisan would appreciate that a wide variety of salts would function in this transformation. In addition, a wide variety of carboxylic acids would react to provide compounds of Formula IIA. Most preferably the salts are purified and dried shortly before use, or may be alternatively be fused before use and the reaction performed with sonication. The reaction time is typically from about 1-48 hours, most preferably about 24 hours. The reaction is typically performed at room temperature but may be performed a temperatures ranging from xe2x88x9278xc2x0 C. to the reflux temperature of the solvent. As stated above, the choice of solvent is not critical and may be determined by cost or convenience. Preferred solvents include toluene and THF and preferably the reaction solvent is approximately a 2:1-1:1 mixture of toluene and THF. In addition, the reaction is preferably performed in the dark with dry solvents to minimize undesired side reactions.
Thermal Cyclization 
The inventors have surprisingly discovered that compounds of Formula IIA cyclize to compounds of Formula I under thermal conditions. This type of thermal cyclization is unprecedented in the literature and has tremendous advantages over methods currently practiced in the art which require expensive catalysts that are cumbersome to utilize and a problem to dispose of safely.
The thermal cyclization occurs by heating a compound of Formula IIA to a temperature of from about 40xc2x0 C. to about 200xc2x0 C. The reaction can be performed neat or in the presence of a solvent. The reaction is preferably performed neat under vacuum. Conducting the reaction under vacuum has the advantage that the succinimide produced in the synthesis the compounds of Formula IIA sublimes from the reaction mixture. The preferred reaction temperature is about 55xc2x0 C. The preferred reaction time is from about 0.5 hours to about 24 hours. The skilled artisan will appreciate that the rate of the reaction and production of side products will vary depending on the temperature and duration of the reaction. Preferred temperatures and duration of reaction will vary depending on the particular substrate of Formula IIA.
Transformation to Cephalosporin Antibiotics
The product 3-methylenecephems sulfoxides of the process of this invention are useful intermediates in the preparation of cephalosporin antibiotics. 
The sulfoxides of Formula I can be reduced by known procedures, typically with phosphorous trichloride or phosphorous tribromide in dimethylformamide, to provide the corresponding 3-methylenecephems which are predictably converted to desacetoxycephalosporins of Formula IV, upon treatment with triethylamine in dimethylacetamide. [Chauvette and Pennington, J. Org. Chem., 38, 2994 (1973)]. The desacetoxycephalosporin esters are converted to active antibiotics of Formula V, by cleaving the ester function. Deprotection of the acid functionality is well known in the art and the procedures will vary depending on the specific protecting group.
Alternatively the exomethylenecephams can be employed in the preparation of other cephem antibiotics of the formula VI; 
Wherein A may be but is not limited to chloro, bromo, methoxy, triflyl, triflyloxy, mesyl, tosyl, hydrogen, thioether, alkyl, alkenyl, or aryl.
Such chemical conversions, as well as too many others to mention, have been disclosed in the art and are well known. [see e.g. Chauvette and Pennington, JACS., 96, 4986 (1974).] For a review of 3-chlorocephem and other 3 derivatives see, The Chemistry and Biology of Betalactam Antibiotics, vol. 1, edited by, Morin and Gorman, Academic Press, 1982 Chapter 2, p 93. (See also; Tetrahedron Letters, 6043, 1988. Heterocycles, 23, 1901, 1985. J. Organic Chemistry, 54, 4962, 1989. J. Organic Chemistry, 54, 5828, 1989. Tetrahedron Letters, 3389, 1990. Synthetic Communications 20, 2185, 1990. Tetrahedron Letters, 4073, 1991. J. Organic Chemistry, 58, 2296, 1993. Tetrahedron Letters. 7229, 1993. J. Antibiotics, 47, 453, 1994. J. Antibiotics, 44, 498, 1991. Helv Chim Acta, 60, 1510, 1977.)
In general, the exomethylenecephem compounds maybe converted by low temperature ozonolysis, to 3-hydroxycephems or the 3-keto equivalents which are in turn treated with diazomethane at room temperature to afford the 3-methoxycephem derivatives. The 3-halocephems are derived from the 3-hydroxycephem esters by treatment with a halogenating agent such as thionyl chloride, phosphorous trichloride, or phosphorous tribromide by methods known in the art. The corresponding deprotected cephem acids exhibit antibacterial activity. The 3-hydroxy group can also be converted into the triflyloxy compound which can then be converted into many different 3-carbon substituted cephems or many different thio substituted cephems.